DESCRIPTION (provided by investigator): This application addresses the broad Challenge Area: 08: Genomics, and the specific Challenge Grant Topic: 08-AG-105**: Approaches to study the interactions among individual behaviors, social and physical environments, and genetic/epigenetic processes during critical developmental periods. Project Title: Early Life Exposures before Birth and Adult Epigenetics Extensive epidemiologic evidence has linked many early life and environmental factors to adult- onset diseases. One plausible mechanism how the environment could alter disease risk later in life is through epigenetic effects on somatic cells, leading to activation or silencing of key genes in critical pathways. DNA methylation, one type of epigenetic change, may play an important role in disease causation by altering the proteins that are produced by genes. Thus, people with identical genes, like twins, may have different disease outcomes because of differential changes in DNA methylation that affect the ability of specific genes to produce specific proteins. Human studies have supported that DNA methylation patterns change with age and animal studies have supported that exposures during critical periods can alter epigenetic events. However, until now, there have been few opportunities to link these two lines of evidence in humans by examining exposures during critical periods including the prenatal and early life periods and DNA methylation patterns latter in life. We have recently completed the first study in humans showing associations between early life factors such as birth weight and genomic DNA methylation measured in mid-life among women in a multiethnic birth cohort (1) and also the first study to show that there are persistent epigenetic differences in DNA methylation of the IGF2 gene after exposure to a prenatal famine environment (2). Using resources from an adult follow-up already collected from three birth cohorts in the Netherlands with prenatal famine exposure in born in 1944-1945 and from unexposed time controls and sibling controls (n= 971;437 men and 537 women), we now propose to examine the associations between maternal famine exposure in the periconceptional period and in different stages of pregnancy on the one hand and DNA methylation patterns in adulthood on the other. We will further examine how the DNA methylation patterns in adulthood are related to disease risk factors for cardio-vascular disease and diabetes such as obesity, elevated blood cholesterol or fasting glucose values. Because some studies suggest that the relation between the early environment and long-term health outcomes may be different in men and women, we will compare these patterns by gender. The field of epigenetics holds great promise in helping us understand the basis of human disease and in particular how environmental exposures can get inside the body to cause disease. Epigenetics may also help explain differences in disease across populations and therefore may be important in understanding how environmental exposures may contribute to health disparities. Conducting large epidemiologic studies with robust measures of exposures based on information already collected in the past during critical periods combined with reliable markers of DNA methylation today are a necessary first step. Such studies can only be conducted by multidisciplinary teams with an understanding of biological mechanisms and methodological issues. Our team has extensive expertise in the design and analysis of life course studies in the US and abroad and is very experienced in dealing with the many methodological issues of critical periods, DNA methylation, and multiple disease outcomes. This challenge grant in addition to accomplishing the scientific aims will support the retention of a senior laboratory scientist with expertise in DNA methylation assays and two Masters level analysts with expertise in statistics and life course methods respectively, as well as provide funding to the investigator team to now include epigenetic approaches in their ongoing analyses of these unique birth cohorts. This will be highly relevant for the continuing investigation of the lifelong impact of even early lifetime exposures on health. A growing body of evidence indicates that epigenetic changes, including DNA methylation, may play an important role in the development of cardiovascular disease, cancer and other chronic conditions. In contrast to genes, epigenetic patterns may be affected by the environment and change over the life course. Further, epigenetic patterns may be reversed through changes in risk factors, as both human and animal studies have reported associations between prenatal and early life exposures and DNA methylation in adulthood. PUBLIC HEALTH RELEVANCE: This study will make use of a prospective birth cohort of women and men born in 1944-1945 to examine in the next two years whether the prenatal environment and specifically maternal nutrition in pregnancy are associated with changes in genomic DNA methylation levels in adulthood. We will further investigate if genomic DNA methylation levels in adulthood are associated with clinical indicators for cardiovascular disease risk such as blood pressure, lipid levels, fasting blood sugar levels, and obesity. The required medical examination records and biological materials for this study have been previously collected and stored and pending funding will be immediately available for analysis.